tbuckley/cabot-search huggingface dataset:
An invertebrate model for TMEM43-induced arrhythmogenic right ventricular cardiomyopathy (ARVC) type 5
Authors: N Klinke, M Reinhardt, S Ratnavadivel, H Harten, A Malmendal, H Milting, A Paululat
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG Objectives TMEM43 encodes for a transmembrane protein located in the ER membrane and the nuclear rim. TMEM43 has predicted four transmembrane domains. The missense variant TMEM43 p.S358L is fully penetrant in males and associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) type 5. Even though, TMEM43 is a phyllogenetically conserved protein throughout different species, little is known on the molecular mechanism of the mutation. TMEM43 is highly homologous to the single CG8111 gene in Drosophila melanogaster. The clincal relevant amino acid serine at position p358 is situated in the third transmembrane domain, the same applies to the corresponding amino acid p.S333L in the Drosophila homologue. Here, we established the first invertebrate model to study the pathophysiological effects of the human variant in the Drosophila homologue CG8111. Methods To investigate the effect of this missense mutation in flies, we introduced the variant CG8111 p.S333L in Drosophila and overexpressed the mutant variant CG8111p.S333L in transgenic flies, either ubiquitously or in a tissue specific manner. Cardiac specific physiological effects of the mutant variant were examined by Semi-automatic Optical Heartbeat Analysis (SOHA) for heart rate, systolic and diastolic interval, fractional shortening and arrhythmicity index. Mutant and wildtype flies were further compared by mass-spectrometry for differentially regulated proteins. Metabolites were analysed by NMR accordingly. Results Our studies showed that in comparison to the wild type the ubiquitously overexpressed variant leads to lethal effects at pupal stages. Individuals died from reduced food uptake and excessive lipid droplet accumulation in adipocytes. CG8111p.S333L animals up-regulate proteins, involved in fatty acid metabolism pathways. Metabolomic data revealed increased amounts of fatty acids accumulation in mutant versus wild-type animals. Furthermore, heart specific overexpression of CG8111p.S333L was associated with arrhythmias in five week old male flies. Conclusions CG8111p.S333L overexpression is a lethal genotype in Drosophila. Our data suggest a metabolic dysfunction associated with the mutant form of CG8111p.S333L, which shares pathophysiological characteristics of the human condition in TMEM43 p.S358L carriers.
Simulation modeling as a tool to support clinical guidelines and care for breast cancer prevention and early detection in high-risk women.
Authors: Jinani Jayasekera, Kathryn P. Lowry, Jennifer M Yeh, Marc D Schwartz, Karen J Wernli, Claudine Isaacs, Allison W. Kurian, Natasha K. Stout
Journal: Journal of Clinical Oncology (2022)

10525 Background: To evaluate the incremental short- and long-term benefits and harms of primary prevention with risk reducing medication in high-risk women receiving screening mammography. Methods: We adapted an established, validated Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer discrete event microsimulation model developed to synthesize data the impact of using risk-reducing medication and annual mammography among women with a 3% or higher five-year risk of developing breast cancer. We also examined the effects of supplemental MRI. The model follows a simulated cohort of millions of US women from birth to death. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, breast cancer risk, incidence and stage, screening performance, survival by age, stage, and subtype, treatment efficacy, and other cause mortality. Breast cancer risk was modeled based on family history, breast density, age and history of past breast biopsy. We compared two strategies, annual 3D mammography alone vs. annual 3D mammography and a 5-year course of risk reducing medication at various starting ages, and adding MRI to each approach. Outcomes included the benefits of risk-reducing drugs (avoiding breast cancer) and screening (stage, breast cancer death). Harms included drug side effects and screening false positives and overdiagnosis. Sensitivity analysis tested the impact of uncertainty in model inputs and assumptions on results. Results: Compared to mammography alone, adding risk reducing medication could decrease invasive breast cancer incidence by 30%, and breast cancer deaths by 30% (Table). However, due to reduction in breast cancer incidence, risk reducing medication could result in a 3% increase in false positive results; adding MRI increases benefits but also increases false-positive results. Benefits and harms of risk reducing medication and breast cancer screening strategies for women at high-risk of developing breast cancer. Conclusions: Risk-reducing mediation reduces the risk of hormone-receptor positive breast cancer, and combining this with mammography (and/or MRI) improves earlier detection. Additional work is ongoing to incorporate adverse effects of therapy. Simulation modeling can be used to provide individualized data to facilitate discussions about breast cancer prevention and early detection among high-risk women seen in clinical practice.[Table: see text]
Hypoxic preconditioning effects change in hypertrophied or insulin resistant rat hearts
Authors: V Babicheva, M Kozlovska, M Vasylenko, A Portnychenko
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education and Science of Ukraine Purpose Cardioprotective mechanisms in the hypertrophied or insulin resistant heart is not fully elucidated. Insulin like growth factor IGF-1 through downstream kinases PI3K/Akt/GSK3beta is known to exert cardioprotective effects and regulate myocardial remodeling, glucose metabolism, cell survival, apoptosis, oxidative stress etc. The aim was to characterize IGF-1/PI3K/Akt-mediated cardioprotection in hypertrophied or insulin resistant hearts after hypoxic preconditioning in response to severe whole body hypoxia or isolated heart ischemia/reperfusion. Methods Experiments were performed in male adult Wistar rats, and SHR with long-term heart hypertrophy. Insulin resistance (IR) was induced by high fat diet (58% kcal from fat). The animals were exposed to hypoxic preconditioning using mild hypobaric hypoxia séances in barochamber (5600 m, 3 h). In 24 h, hearts were isolated with urethane narcosis and subjected to ischemia/reperfusion in a Langendorff mode, infarct size was detected with TTC staining. The other group of rats after preconditioning were subjected to severe hypoxia (9000 m, 3 h). Inhibitor of PI3K wortmannin or blocker of IGF-1R picropodophyllin were used for testing of cytoprotective signalling. Protein expression were examined using Western blotting. Results In SHR, the myocardial expression of IGF-1 and Akt was lower by 42% or 63%, respectively, compared to Wistar. IR increased GSK-3beta expression and phosphorylation. Hypoxic preconditioning intensified IGF-1/PI3K/Akt-mediated cardioprotection, less pronounced in hypertrophied or insulin resistant hearts. Blockade of PI3K or IGF-1Rdecreased Akt phosphorylation, and abolished cytoprotective effects of preconditioning in view of mortality caused severe hypoxia, or of infarct size and cardiac function recovery in postischemic reperfusion. In SHR, hypoxia-induced cardioprotective effects and influences of the blockers were significantly reduced. Conclusions The long-term left ventricular hypertrophy is accompanied with reduction of IGF-1/IGF-1R/PI3K/Akt-dependent prohypertrophic and cardioprotective signalling. Hypoxic preconditioning mediated by IGF-1/PI3K/Akt-signalling loses its effectiveness during prolonged cardiac hypertrophy, as well as insulin resistance development.
The role of transjugular intrahepatic portosystemic shunt in patients with cirrhosis and ascites: Recent evolution and open questions
Authors: Pierre Deltenre, Alberto Zanetto, Dario Saltini, Christophe Moreno, Filippo Schepis
Journal: Hepatology (2022)

In selected patients with cirrhosis and ascites, transjugular intrahepatic portosystemic shunt (TIPS) placement improves control of ascites and may reduce mortality. In this review, we summarize the current knowledge concerning the use of TIPS for the treatment of ascites in patients with cirrhosis, from pathophysiology of ascites formation to hemodynamic consequences, patient selection, and technical issues of TIPS insertion. The combination of these factors is important to guide clinical decision‐making and identify the best strategy for each individual patient. There is still a need to identify the best timing for TIPS placement in the natural history of ascites (recurrent vs. refractory) as well as which type and level of renal dysfunction is acceptable when TIPS is proposed for the treatment of ascites in cirrhosis. Future studies are needed to define the optimal stent diameter according to patient characteristics and individual risk of shunt‐related side effects, particularly hepatic encephalopathy and insufficient cardiac response to hemodynamic consequences of TIPS insertion.
The association between BIM deletion polymorphism and treatment efficacy of PD-1/PD-L1 inhibitors in advanced NSCLC.
Authors: Dai Zhang, Xuanzong Li, Caimei Huang, Xinyu Fan, Wenru Qin, Linlin Yang, Linlin Wang
Journal: Journal of Clinical Oncology (2022)

e21055 Background: PD-L1 is a recommended biomarker for immunotherapy, but Some patients with high pD-L1 expression had poor clinical response. Considering the inconsistent correlation between PD- L1 expression and ICI efficacy, A more sensitive biomarker is needed to predict immunotherapy efficacy. B-cell lymphoma-2 (BCL2L11/BIM) belongs to the Bcl-2 family and is a key factor promoting apoptosis. BIM deletion polymorphism (BIM- del) may lead to BH3 deletion and thus hinder cell apoptosis. Loss and decreased expression of BIM may lead to resistance to tumor therapy. A study on patients with metastatic melanoma found that the high level of BIM in CD8+ T cells suggests a stronger PD-1 and PD-L1 interaction, which predicts clinical benefit in patients with metastatic melanoma receiving anti-PD-1 therapy.This study aims to evaluate the relationship between BIM deletion and PD-1/PD-L1 inhibitors efficacy in advanced NSCLC patients. Methods: Patients diagnosed with advanced stage NSCLC that treated with Immune checkpoint inhibitors (ICIs) at Shandong Cancer Hospital between March 2019 and January 2021 were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del. Results: A total of 61 patients with advanced NSCLC who received immunotherapy were enrolled, only 18.0% (11/61) patients were detected with BIM-del. Most of the patients were male (73.8%, 45/61), younger than 65 years (72.1%, 44/61), non- smokers (50.8%, 31/61), previous treatment lines 0-1 (90.2%, 55/61),had Eastern Tumor Cooperative group (ECOG) performance status (PS) 0-1 (98.4%, 60/61). There were no associations between the BIM-del and clinical characteristics. There was no difference in the objective response rate between patients with and without BIM-del (27.3% vs 30 %, p = 1.000).BIM-del is associated with shorter progression-free survival (PFS) (5.7 months vs12.0 months, p = 0.001). The median OS had not been reached. Multivariate analysis suggested that BIM-del was an negative independent prognostic factor for PFS in immunotherapy patients with non-small cell lung cancer, but not for OS. Conclusions: BIM-del may be a negative prognostic biomarker for patients with advanced NSCLC treated with immunosuppressive therapy. It is very important to find effective and accurate biomarkers to predict the PD-1/PD-L1 inhibitors Treatment efficacy, and further exploration is needed in the future.
Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis
Authors: Jinyuan Luoqian, Wenyong Yang, Xulong Ding, Qing-zhang Tuo, Zheng Xiang, Zhaoyue Zheng, Yu-jie Guo, Li Li, Pengbo Guan, Scott Ayton, Biao Dong, Huiyuan Zhang, Hongbo Hu, Peng Lei
Journal: Cellular and Molecular Immunology (2022)
SCOUT-1: Prospective non-interventional study in patients with <i>BRCA</i>/HRD-tested ovarian cancer (OC) eligible for first-line (1L) platinum-based chemotherapy (NOGGO ov54).
Authors: Pauline Wimberger, Klaus Pietzner, Ioana Braicu, Regina Glowik, Matthias Rose, Jalid Sehouli
Journal: Journal of Clinical Oncology (2022)

TPS5608 Background: Two third of patients with OC, have an advanced stage at initial diagnosis accompanied with poor prognosis. Results from landmark trials of maintenance therapy (MTX) with poly ADP ribose polymerase inhibitors (PARPi), especially in tumors associated with homologous recombination deficiency (HRD), like BRCA-mutated tumors, led to the strong recommendation on testing and treatment procedures in the clinical routine in patients newly diagnosed with advanced high-grade epithelial OC. The translation of these guidelines into clinical routine affects care management and therefore needs to be evaluated. This study aims to gain new insights into current real-world biomarker testing and 1L-treatment patterns together with clinical and patient-reported outcomes of patients with newly diagnosed advanced OC in Germany and to capture the influence of 1L treatment (with or without PARPi MTX) on medical routine and patient needs. Methods: SCOUT-1 is a national prospective, observational study (NCT04830709) to collect clinical real-world and patient-reported outcome (PRO) data in patients newly diagnosed with histologically confirmed advanced (FIGO stage III or IV) high-grade epithelial ovarian, fallopian-tube, or primary peritoneal cancer in Germany. Selection criteria include written informed consent, completed surgery (if applicable), eligible for platinum-based chemotherapy, BRCA1/2 mutation tested and willingness/ability to report PROs electronically. About 750 patients are planned to be included in up to 80 sites (hospitals or office-based). The primary objective is to determine the effectiveness of standard treatment sequences by estimating progression-free survival according to investigator’s assessment. Further focus is to describe biomarker-testing algorithm, patient selection and to assess patients’ QoL, symptoms, needs, as well as patients’ expectations. Importantly, SCOUT-1 will help to collect long-term data as patients will be followed for up to 7 years. First-subject-was included in the study in June 2021. Study completion date is planned in Q2 2032.
Distinct genomic and immunophenotypic features of solid-predominant versus nonsolid-predominant stage I lung adenocarcinomas and association with disease recurrence after surgical resection.
Authors: Joao Victor Machado Alessi, Zihan Wei, Biagio Ricciuti, Victor R. Vaz, Adriana Paula de Castro Barrichello, Giuseppe Lamberti, Bijaya Sharma, Kathleen L. Pfaff, Kristen Felt, Madison M. Turner, Scott J. Rodig, Lynette M. Sholl, Mark M. Awad
Journal: Journal of Clinical Oncology (2022)

8514 Background: Compared to lung adenocarcinomas (LUAD) with nonsolid-predominant histology (lepidic, acinar, papillary, micropapillary), those with predominantly solid features have a higher risk of disease recurrence after surgical resection. However, little is known about the genomic landscape and immunophenotype of solid vs nonsolid stage I LUAD. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition), which underwent next-generation sequencing to identify genomic alterations and tumor mutational burden (TMB). A subset of these samples also had multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 to determine differences in tumor immune cells subsets according to histologic subtype. Disease free-survival (DFS) was compared in patients based on their predominant histologic subtype (solid vs nonsolid). Results: Among 658 LUADs, 11.4% (N = 75) had solid-predominant and 88.6% (N = 583) nonsolid-predominant histology. After a median follow-up of 50 months from the time of surgery, 145 patients (22.0%) experienced recurrence. Compared to nonsolid-predominant LUAD, those with solid predominance had a significantly lower prevalence of activating EGFR, BRAF V600E , and METex14 mutations as well as ALK/ RET/ ROS1 rearrangements (9.3% versus 31.6%, P &lt; 0.001), no difference in KRAS G12C frequency (24% versus 16.8%, P = 0.14), a higher TMB (median 12.2 versus 7.2 mutations/megabase; P &lt; 0.001), and a shorter median DFS from the time of surgical resection (43.2 months versus not reached, HR: 3.3 [95% CI: 2.2-4.9], P &lt; 0.001). The detrimental effect of solid-predominant LUAD in DFS remained significant after adjusting for other factors such as tumor stage, surgery type, smoking status, and TMB (HR: 2.66 [95% CI: 1.71-4.11], P &lt; 0.001]. Among LUADs profiled by multiplex immunofluorescence, compared to tumors with nonsolid-predominant subtype (N = 197), those with solid predominance (N = 23) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally (P &lt; 0.001) and at the tumor-stroma interface (P &lt; 0.001). Solid-predominant subtype was also associated with a higher median PD-L1 expression level on tumor (5% versus 1%; P = 0.01) and immune cells (16% versus 7%, P = 0.02). Conclusions: Among patients with surgically-resected stage I LUAD, solid-predominant histology was associated with distinct genotypic and immunologic characteristics. These findings may aid in identifying patients at greater risk of recurrence after surgery.
Identifying disparities in gynecologic cancer: Results and analysis from a patient preference survey.
Authors: Eloise Chapman-Davis, Kimberly J. Halla, Shannon Neville Westin, Ritu Salani, Jerfiz D. Constanzo, Timothy A. Quill, Kathryn Burn, Angeles Alvarez Secord
Journal: Journal of Clinical Oncology (2022)

5561 Background: Health disparities exist in gynecologic cancers, with data revealing lower survival among certain racial/ethnic groups. Studies suggest underrepresented patients of color with gynecologic cancers may not receive guideline-concordant care to adequately manage their disease, including molecular testing. We conducted a patient preferences survey evaluating treatment choices and provider interactions influencing adherence to guideline-based care. Methods: From July 7 to August 18, 2021, a survey was sent to women with gynecologic cancers who participate in the SMART Patients advocacy group. Survey questions covered topics of preparedness to discuss care with provider, biomarker testing specific to gynecologic tumor type, patients’ considerations informing treatment choices, and confidence to work with providers to improve their clinical and survival outcomes. Information regarding cancer diagnosis, stage, race, ethnicity, treatment, and genetic testing was obtained. Survey responses between non-Hispanic White patients (W) versus non-White (NW) underrepresented patients of color were compared and analyzed using descriptive statistics. Results: A total of 89 women with gynecologic cancers (67% ovarian, fallopian tube, and peritoneal; 21% endometrial; 9% vulvar or vaginal; and 2% cervical) participated in the patient survey. Amongst responders, 55% had localized disease while 36% indicated they had metastatic disease, and 9% did not know. Overall, 86.5% were W and 13.5% were NW (Asian, Black/African American, Native American or Pacific Islander, Hispanic, or mixed race). A higher proportion of NW compared to W patients said they were not at all prepared to discuss cost of treatment (18.2% vs 9.5%), treatment options (12.5% vs 4.5%), and side effects of treatment (20% vs 0%) with their provider; 31% of W patients discussed genetic testing and received resources from their provider compared with only 16.7% of NW patients, and a higher proportion of NW compared to W patients (37.5% vs 28.1%) indicated they were not confident in their ability to work with providers to improve their cancer treatment outcome. Conclusions: While a limitation of this study was low participation from diverse populations, the findings indicate that underrepresented NW patients felt less prepared to discuss treatment-related issues compared to W patients. Moreover, a large proportion of all patients with OC were not informed and/or aware about genetic testing, and approximately a third of participants were not confident in their ability to interact with provider to improve their outcomes. The results highlight opportunities to enhance health care provider education and community outreach to reduce gaps in care delivery.
Selective internal radioembolization (SIRT) allows to control liver metastases of gastrointestinal stromal tumors (GIST) failing treatment with tyrosine kinase inhibitors (TKI).
Authors: Peter Hohenberger, Nils Rathmann, Karen Buesing, Franka Menge, Peter Reichardt, Stefan O. Schoenberg, Steffen Diehl
Journal: Journal of Clinical Oncology (2022)

11540 Background: The liver and the peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH (‘wildtype’) or after treatment with 1 st /2 nd /3 rd /4 th line therapy, interventional radioembolization with yttrium-90 ( 90 Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients Methods: From 1/2008 to 1/2018, 2^6 pts (12f, 14m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2 nd mutation (n = 7), exon 9 (n = 3), exon 9+2 nd mut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 33.6 mos (range, 12-108mos) and all patients were followed until death Results:.The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 10.7-23.8 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p &lt; 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in earlier treatment lines.